The Watanabe heritable hyperlipidemic (WHHL) rabbit has a genetic defect in the low density lipoprotein (LDL) receptor. Rabbits homozygous for this defect exhibit spontaneous hyperlipidemia on a low fat diet, atherosclerosis, tendon xanthomas, a markedly decreased number of LDL receptors in several tissues, and impaired LDL catabolism in vivo. Therefore there are striking similarities between this animal model and the human disease, Familial Hypercholesterolemia. The long term objective of this project is to explore the derrangements in lipoprotein metabolism that result from an LDL receptor deficiency in the WHHL rabbit. Alterations in lipoprotein composition resulting from this genetic defect will first be defined. Using radiolabeled lipoproteins, derrangements in lipoprotein metabolism will be studied in an attempt to understand the pathogenesis of the hyperlipidemia. Radiolabeled LDL will be used to study alterations in tissue uptake of this lipoprotein in the absence of functioning LDL receptors. This approach will also be used to better define the role of the reticuloendothelial system (RES) in LDL catabolism when LDL receptors are not present. Finally, the impact of the LDL receptor deficiency on total body cholesterol metabolism will be explored using standard cholesterol balance techniques. Since an LDL receptor deficiency state is associated with hyperlipidemia and spontaneous atherosclerosis in two species as different as the rabbit and the human, a delineation of the lipoprotein abnormalities resulting from this receptor defect in the rabbit should enhance our understanding of similar factors contributing to atherosclerosis in the human.